Cowen Healthcare presentation March 13th 2018

Transcription

1 Cowen Healthcare presentation March 13th 2018

2 Disclaimer The information contained in this presentation is being supplied and communicated to you on a confidential basis solely for your information and may not be reproduced, further distributed to any other person or published, in whole or in part, for any purpose. The distribution of this presentation in certain jurisdictions may be restricted by law, and persons into whose possession this presentation comes should inform themselves about, and observe, any such restrictions. Although reasonable care has been taken to ensure that the facts stated in this presentation are accurate and that the opinions expressed are fair and reasonable, the contents of this presentation have not been verified by Silence Therapeutics plc (the Company ) or any other person. Accordingly no representation or warranty, express or implied, is made as to the fairness, accuracy, completeness or correctness of the information and opinions contained in this presentation and no reliance should be placed on such information or opinions. None of the Company, or any of its respective members, directors, officers or employees nor any other person accepts any liability whatsoever for any loss howsoever arising from any use of such information or opinions or otherwise arising in connection with this presentation. No part of this presentation, or the fact of its distribution, should form the basis of or be relied upon in connection with any contract or commitment or investment decision whatsoever. This presentation does not form part of any offer of securities, or constitute a solicitation of any offer to purchase or subscribe for securities or an inducement to enter into any investment activity. 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Although not exhaustive, the following factors could cause actual results to differ materially from those the Company expects: difficulties inherent in the discovery and development of new products and the design and implementation of pre-clinical and clinical studies, trials and investigations, delays in and results from such studies, trials and investigations that are inconsistent with previous results and the Company s expectations, the failure to obtain and maintain required regulatory approvals, product and pricing initiatives by the Company s competitors, inability of the Company to market existing products effectively and the failure of the Company to agree beneficial terms with potential partners for any of its products or the failure of the Company s existing partners to perform their obligations, the ability of the Company to obtain additional financing for its operations and the market conditions affecting the availability and terms of such financing, the successful integration of completed mergers and acquisitions and achievement of expected synergies from such transactions, and the ability of the Company to identify and consummate suitable strategic and business combination transactions and the risks described in our most recent Admission Document. By participating in this presentation and/or accepting any copies hereof you agree to be bound by the foregoing restrictions and the other terms of this disclaimer. Silence Therapeutics

3 Silence Therapeutics - Overview > Developing RNA interference (RNAi) therapeutics, a highly innovative, specific, new class of medicines with life-saving potential for patients with serious and rare diseases > Only quoted European RNAi drug development Company > Proprietary platform technology builds on years of scientific research and in-house know-how > Liver focussed >7,000 genes are expressed in hepatocytes, many of which are therapeutic targets > Validating licensing agreement with Quark Pharmaceuticals > Lead pre-clinical development programme for iron overload disorders (IOD) > Led by an international, sector-experienced Board and Executive Team > 30 people in Berlin (R&D) and 15 people in London (Corporate and R&D) > Explore options to expand our international capital market presence, including the potential for a NASDAQ listing > Traded on the LSE:AIM 138 million/$190 million mkt cap* with strong cash runway ( 43 million as of 2 January 2018) * 5 March 2018 price & conversion Silence Therapeutics

4 Experienced Leadership Team: Strong Background in Discovery & Development of RNA Therapies Ali Mortazavi, Chief Executive Officer Torsten Hoffmann, Ph.D. Chief Operating Officer David Ellam, Chief Financial Officer Since 2012 Since 2017 Since 2016 Dmitry Samarsky, Ph.D. Chief Scientific Officer Laura Roca-Alonso, Ph.D. Head of Corporate Development Michael Mulqueen, Head of BD & Licensing Since 2016 Since 2014 Since 2017 Alison Gallafent, Head of Intellectual Property Ulrich Zugel, Ph.D. Head of Pre-Clinical Drug Discovery Linnea Elrington, Head of Human Resources Since 2017 Since 2016 Since 2017 Silence Therapeutics

5 GalNAc-siRNA Platform Technology Silence Therapeutics

6 GalNAc-siRNA Medicines Schematic structure of our therapeutic molecules: Linker Binds sirna to delivery moiety Chemical modifications A C G U U C G A C C G A A G U C A U G C A A G C U G G C U U C A G U sirna Mediates gene silencing GalNAc (N-Acetylgalactosamine) Mediates targeted delivery to hepatocytes How do we ensure that our medicines are protected and free to use? > GalNAc as a targeting ligand per se is free to use > We have a robust position for our foundational chemical modification technology > We patent our linker chemistries > We patent our potent and highly specific sirna constructs and lead sequences Silence Therapeutics

7 Platform Performance Platform technology: GalNAc-siRNA, able to mediate highly specific gene silencing in hepatocytes (liver) Specificity upon specificity ~7,000 genes operate in the liver. We can target any of them by adapting the sirna sequence, using the same technology Target 1 Target 2 Target 3 Target 4 Normalised target mrna CTRL sirna 1 Normalised target mrna PBS sirna 2 Normalised target mrna CTRL sirna 3 Normalised target mrna CTRL sirna 4 We are able to reproducibly silence disease-causing genes using our platform technology Single SC dose of 2-3 mg/kg in healthy mice; analysis after 1-2 weeks Silence Therapeutics

8 Advantageous Properties of Medicines > Subcutaneous administration, patient friendly > Long duration of action (variable depending on target gene) > Well tolerated > Our GalNAc-siRNA medicines are suitable for a wide range of indications Target KD induction Trend toward recovery to baseline levels NADIR Silence Therapeutics

9 SLN124 for the treatment of Iron Overload Disorders A case study of our platform Silence Therapeutics

10 Treatment of Ion Overload Disorders (IOD) GOAL > Provide an effective and safe novel treatment option for patients with iron overload conditions, such as β-thalassemia RATIONALE > Target a key modulator in iron regulation with a GalNAc-siRNA molecule providing a highly specific, effective & safe option through inhibition of a disease relevant target gene expressed in hepatocytes CURRENT STAGE > Preclinical development with plans to enter clinical development in Q4/2018 Silence Therapeutics

11 TMPRSS6 is a Negative Regulator of Hepcidin and Plays a Key Role in Iron Homeostasis Normal hepcidin levels control iron release from cellular stores & intestinal uptake Liver TMPRSS6 Duodenal Enterocytes Low hepcidin levels, as in asβ-thalassemia in result in high iron levels & overload in organs Liver TMPRSS6 Duodenal Enterocytes Hepcidin IRON SLN124 Hepcidin IRON Macrophages Erythropoiesis Macrophages Erythropoiesis Red blood cells Red blood cells Silencing TMPRSS6 1 Increases hepcidin levels 2 Reduces iron 3 Improves 4 levels erythropoiesis Reduces organ iron overload TMPRSS6 = Transmembrane Protease, Serine 6 Silence Therapeutics

12 sirna Screen and GalNAc Conjugate Testing in Primary Hepatocytes Normalised TMPRSS6 mrna TMPRSS6 mrna (in vitro screen Selected sirnas) h Hep3B cells Lead UTLuc TMPRSS6 sirna Normalised TMPRSS6 mrna Normalised TMPRSS6 mrna Hep (mouse) GalNAc TMPRSS6 sirna [nm] 1 Hep (human) GalNAc TMPRSS6 sirna [nm] TMPRSS6 mrna (receptor-mediated uptake) Normalised TMPRSS6 mrna Hep (cyno) GalNAc TMPRSS6 sirna [nm] > Lead sirna for TMPRSS6 identified (picomolar IC50 by transfection) > GalNAc-siRNA conjugate is functional in primary hepatocytes from different species (mouse, human, cynomolgus) Silence Therapeutics

13 Silencing TMPRSS6 Lowers Serum Iron Levels in Mice d1 Study design d4 SC, n=4-6 mice TMPRSS6 mrna (liver) Hepcidin mrna (liver) Iron (serum) 4 40 Normalised TMPRSS6 mrna Normalised Hepcidin mrna Serum iron [µmol/l] CTRL 1 3 TMPRSS6 10 m g/kg sirna 0 10 CTRL 1 3 TMPRSS6 10 m g/kg sirna 0 10 CTRL 1 3 TMPRSS6 10 m g/kg sirna >Single subcutaneous administration results in specific KD of TMPRSS6 >Upregulated Hepcidin causes reduction of blood iron levels >Proof of mechanism demonstrated Silence Therapeutics

14 SLN124 Lowers Iron Levels for at Least 6 Weeks After Single Administration in Mice Study design d1 wk 1 wk 3 wk 6 SC, n=4 mice, 3 mg/kg TMPRSS6 mrna (liver) Iron (serum) 40 Normalised TMPRSS6 mrna Serum iron [µmol/l] PBS 1 3 TMPRSS6 sirna 6 weeks 0 1 PBS 1 3 TMPRSS6 sirna 6 weeks >Long-lasting functional mrna KD in liver >Reduction of serum iron levels for at least 6 weeks >Well tolerated with long duration of action in mice Silence Therapeutics

15 Therapeutic Activity of SLN124 in Iron Overload Model (HFE -/- mice) Collaboration with Prof. Dr. Martina Muckenthaler University of Heidelberg, Germany Study design d1 wk 3 SC, n=6-7 mice TMPRSS6 mrna (liver) Hepcidin (serum) Iron (serum) Normalised TMPRSS6 mrna PBS 3 CTRL 1 3 TMPRSS6 m g/kg sirna Serum Hepcidin [ng/ml] PBS 3 CTRL 1 3 m g/kg TMPRSS6 sir N A Serum Iron [µg/dl] PBS 3 CTRL 1 3 m g/kg TMPRSS6 sir N A 240 Iron (kidney) > Dose-dependent and robust silencing of TMPRSS6 mrna in the liver [µg Iron/g dry tissue] > Increase in serum hepcidin levels > Reversion of serum and kidney iron levels to physiological values 0 PBS 3 CTRL 1 3 m g/kg TMPRSS6 sirna Silence Therapeutics

16 SLN124 Normalises ROS Species & Improves RBC Parameters in β-thalassemia Disease Model Collaboration with Prof. J. Vadolas & Dr. Grigoriadis Monash Medical Centre/Melbourne, Australia Study design d1 wk 2 wk 5 SC, n=6-8 Hbb th3/+ mice Reactiveoxygen species (ROS) Reticulocyte proportion Haematocrit Median FI Reticulocytes [%] Haem atocrit [% ] W T m ic e PBS 0 CTRL TMPRSS6 sirna - T h 3 /+ m ic e W T m ic e PBS 0 CTRL TMPRSS6siRNA - T h 3 /+ m ic e W T m ic e PBS CTRL TMPRSS6 sirna T h 3 /+ m ic e > Normalisation of ROS to levels in healthy mice > Normalisation of reticulocyte proportion and improvement of haematocrit > SLN124 significantly improves erythropoiesis in animal model for β-thalassemia intermedia ROS = reactive oxygen species; RBC = red blood cells Silence Therapeutics

17 Feedback by Key Opinion Leaders on SLN124 International KOL workshop with clinical and regulatory experts in the field of iron overload disorders > High medical need to reduce iron overload and number of transfusions in patients > Not met by currently available therapies > SLN124 has the potential to > Reduce systemic iron > Prevent organ iron overload > Enhance erythropoiesis... providing a significantly improved therapeutic option and better quality of life for patients living with iron overload conditions, such as β-thalassemia Silence Therapeutics

18 Market Opportunity of SLN124 (US & Europe) β-thalassemia intermedia & T. major (TDT) >Combination with transfusions & chelators to reduce frequency & dose >Improve erythropoiesis and reduce secondary iron overload burden β-thalassemia intermedia (NTDT) >Monotherapy to delay onset of severe symptoms >Reduce dietary iron overload & subsequent organ damage Other iron overload disorders Myelodysplastic Syndrome (MDS) Haemochromatosis 40,000 TDT 20,000 NTDT >150,000 MDS >3,000,000 Haemochromatosis *US & Europe SLN124 for β-thalassemia withsignificant upside potential for other iron overload disorders TDT = transfusion dependent Thalassemia; NTDT = non-transfusion dependent Thalassemia Silence Therapeutics

19 Why we are Excited about SLN124? Science Indication Patient Market What does the Mode of action bring? How does the science connect to the diseases? What is the patient benefit? When and where do we want to market it? 2018: Gene silencing via sirna is a proven concept SLN124 has proven to increase hepcidin and reduce iron plasma levels, thus restoring iron homeostasis The GalNAc conjugate targets hepatocytes in the liver, acting specifically at hepcidin s predominant synthesis site SLN124 is highly specific targeting a single gene beta-thalassemia Myelodysplastic Syndromes Potential for Haemochromatosis Central role of hepcidin enables lowering of iron plasma levels, optimising erythropoiesis Mechanistic claim treatment of iron overload disorders SLN124: a treatment in the mono- or combination therapy setting as new SoC SLN124 has the potential to become an essential component of the future SoC QoL parameters will be improved such as transfusion frequency and drug burden of chelators Enables an early treatment option for the prevention of iron deposition in organs Pediatrics and adults will be treated We will work with patient organisations in 2018 First In Class in iron overload High value product with peak sales of $600 million (BT) and $3 billion (MDS) Launch would be expected by 2024/25 via an Orphan designation A corporate strategy is required to access geographies in the middle and far east We are seeking commercialisation partnerships Silence Therapeutics

20 Pipeline - Building a Proprietary Portfolio Internal programmes advanced into preclinical development Our Programmes SLN124 SLN124 4Q2018 Out-Licensed Programmes SLN226 SLN226 Mid 2019 Mid 2019 Silence Therapeutics

21 Platform Strategy ~7,000 accessible gene targets We have the technology and the team to discover and develop a wide range of therapeutics Target & Indication Selection Cost: In silico selection In vitro screen KD in vivo Disease models NCD, CMC, Regulatory POM* ppoc** CTA*** Phase I $ $ $ $ $... We intend to strategically partner our programmes at different stages to fully unlock the value of our platform Rapid path to value creation CTA/IND enabling Disease model (ppoc) Healthy animals (POM) Phase 1/Phase 2 Technology deals * proof of mechanism in healthy mice ** proof of concept in animal disease model *** clinical trial application Silence Therapeutics

22 Outlook: Significant Milestones for the Next 12 months 2018 will be a year of continuity and building upon success to capture value by executing on pipeline development and leveraging its platform > File clinical trial approval for iron overload by end of 2018 > Add further development expertise to the senior team as pipeline progresses > Secure further validating collaborations utilising our GalNAc platform technology > Add new targets to pipeline, and utilise next generation technology > Continue defensive UK litigation action Silence Therapeutics